Emulsion formulation

ABSTRACT

The present invention is related to a pharmaceutical formulation which is an oil-in-water emulsion for parenteral and oral use which comprises 
     (i) an emulsion-stabilizing surface active drug in high concentration; 
     (ii) optionally a pharmacologically inert oil; 
     (iii) optionally a surfactant; 
     (iv) water or a buffer; and 
     (v) an agent giving isotonicity to the final formulation; 
     the use of and a process for preparation of the formulation.

FIELD OF INVENTION

This invention relates to a novel pharmaceutical formulation comprisingan emulsion-stabilizing surface active drug which may be administeredparenterally or orally; and to the use of and a process for preparingsaid formulation.

BACKGROUND OF THE INVENTION

The present commercially available parenterally administered formulationof 5-(2-chloroethyl)-4-methylthiazole, hereafter abbreviated as CMZ, isa 0.8 w/v % solution of the edisilate salt of CMZ in 4 w/v % aqueousglucose. The product is not available in a more concentrated formbecause the incidence of hemolysis and venous thrombophlebitis is thenunacceptably high. The solubility of the active ingredient is also toolow at physiological pH. The low concentration of CMZ may require alarge fluid load if the product is used for a prolonged period of time.This is a problem especially in patients with renal failure and thosewith fluid and electrolyte problems. Hence, the above mentioned problemshave limited the product's usefulness in the clinic. Moreover, thepresence of glucose is contraindicated in the treatment and/orprevention of neurodegeneration. Other undesirable properties of thecommercially available product are the poor stability of theCMZ-edisilate at room temperature (the product must be stored at +4°-8°C.) and the substantial sorption of CMZ by intravenous infusion givingsets. This sorption to plastics results in a safety problem in theclinic, especially when treating disorders requiring very accuratedosing. Finally, the oral liquid dosage form, a 5 w/v % syrup ofCMZ-edisilate, also has a number of disadvantages such as poor stabilityat room temperature and a low level of patient acceptance due to theacidity and bitter taste of the product. There is accordingly a greatneed for an improved product both from a pharmaceutical and clinicalpoint of view.

DESCRIPTION OF THE INVENTION

The problems mentioned above have surprisingly been solved by a novelformulation. Thus, the object of the invention is to provide a novel,clinically and pharmaceutically acceptable and useful formulation whichis an oil-in-water emulsion for parenteral and oral use which comprises

(i) an emulsion-stabilizing surface active drug in high concentration;

(ii) optionally a pharmacologically inert oil;

(iii) optionally a surfactant;

(iv) water or a buffer; and

(v) an agent giving isotonicity to the final formulation.

The present invention is preferably related to emulsion-stabilizingsurface active drugs having an anti-convulsant or sedative-hypnoticeffect or drugs for preventing and/or treating neurodegeneration causedby acute and chronic neuropsychiatric disorders characterised byprogressive processes that sooner or later lead to neuronal cell deathand dysfunction. Such disorders include stroke; cerebral ischaemia;dysfunctions resulting from brain and/or spinal trauma; hypoxia andanoxia, such as from drowning, and including perinatal and neonatalhypoxic asphyxial brain damage; multi-infarct dementia; AIDS dementia;neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, Huntington's chorea, epilepsy, multiple sclerosis andamytrophic lateral sclerosis; brain dysfunction in connection withsurgery involving extracorporeal circulation or in connection with brainsurgery, including endarterectomy of the carotid arteries; and CNSdysfunctions as a result of exposure to neurotoxins or radiation. Thisutility is manifested, for example, by the ability of the claimedformulation to inhibit delayed neuronal death in the gerbil bilateralocclusion model of ischaemia.

Preferred emulsion-stabilizing surface active drugs are the CMZ-basewhich is an oil at room temperature, and/or some analogues thereof whichare oils at room temperature, namely 5-(2-chloroethyl)-4-methyloxazole,5-(2-chloroethyl)-2,4-dimethyloxazole,5-(2-chloroethyl)-2,4-dimethylthiazole or5-(2-chloro-l-hydroxyethyl)-4-methylthiazole or its optical isomers, thesurface active drug functioning, besides having a pharmacologicaleffect, as a stabilizing surfactant or co-surfactant at the largeinterface in an oil in water emulsion system or in another aspect of theinvention, functioning as the actual oil phase in an emulsion system.

The use of this invention is, however, by no means limited to the abovementioned drugs but could also be used to include any other drug whichdisplays suitable amphiphilic and emulsion-stabilizing properties.

A conventional pharmacologically inert oil is included as a component inthe formulation when the emulsion-stabilizing drug is not itself used asthe internal oil phase.

A conventional surfactant is included as a component in the formulationwhen the drug functions as the internal oil phase of the emulsion.

The agent giving isotonicity to the final formulation is preferablyglycerol and/or sorbitol.

By means of the present invention the undesirable properties of both theparenteral and the oral dosage form, mentioned in the background of theinvention, can be avoided. Certain compounds, because of their chemicalstructure, have a tendency to accumulate at the boundary between twophases. Such compounds are termed amphiphiles, surface-active agents orsurfactants. The adsorption at various interfaces results in fundamentalchanges in the nature of the interface which are of considerableimportance in different contexts. For example, in an emulsion theadsorption of a surfactant at the oil-water interface lowers theinterfacial tension thereby aiding in the dispersal of the oil intodroplets of a small size and helping to maintain the droplets in adispersed state. Unless the interfacial tension is zero, there is atendency for the oil droplets to coalesce to reduce the area ofoil-water contact, but the presence of the surfactant monolayer at thesurface of the droplets reduces the possibility of collisions leading todroplet coalescence and consequently impaired stability of the system.However, not all conventional surfactants display a stabilizing effectsufficient to allow storage for a long period of time (typically twoyears) of pharmaceutically interesting two-phase systems such as forexample emulsions. The geometrical shape of the amphiphilic molecule andthe presence of any substituents in said molecule can have anappreciable effect on its stabilizing properties. Surprisingly, it hasbeen found that e.g. CMZ and said analogues display excellentemulsion-stabilizing properties which allow emulsions of these compoundsto be stored for a long period of time. Due to the geometrical shape andthe amphiphilic properties of the drug molecule it is adsorbed at thesurface of the droplets in the emulsion, forming a rigid and tightlypacked interfacial film thereby reducing the possibility of collisionsleading to droplet coalescence and consequently impaired stability ofthe system.

It has also surprisingly been found that a number of other drugs withhydrophobic portions comprising aromatic and/or heterocyclic ringsystems or a steroid skeleton also display good emulsion-stabilizingproperties.

Examples of the types of drugs, besides CMZ and its analogues, whichhave been found beneficial to use as emulsion-stabilizing agentsinclude: antidepressants, neuroleptics, immunosuppressants,immunomodulators, antibiotics, antiinflammatory agents, proton pumpinhibitors, calcium channel blockers, such as felodipine, and betablockers.

Since it is usually observed that mixtures of conventional surfactantsform even more stable systems than do single surfactants, even with verydilute emulsions, it has in some cases been found beneficial to useemulsion-stabilizing surface active drugs as co-surfactants togetherwith any conventional pharmaceutically acceptable non-ionic surfactants,such as the poloxamers F68, F127 or L92 or polyoxyethylene sorbitanfatty acid esters, polyoxyethylene stearates or sorbitan fatty acidesters; but preferably together with phospholipids, such as egg yolkphospholipids, soya phospholipids, synthetic phosphatidylcholines (e.g.dimyristoyl-phosphatidylcholine (DMPC) and/ordipalmitoyl-phosphatidylcholine (DPPC)) or purifiedphosphatidyl-cholines of vegetable origin. If this principle is fullyused by a person skilled in the art it is possible to manufacture astable two-phase system like e.g. an emulsion of any appropriate drugmentioned above, where the stabilizing effect is due to the surfaceactive drug alone or the surface active drug together with an optionalsurfactant mentioned above, and at the same time making use of the largeinterface in this kind of system to incorporate a high concentration ofsaid surface active drug. In another aspect of the invention, CMZ andthe above mentioned analogues or any other appropriate drug which is inthe liquid state, could also function as the actual oil phase in anemulsion system in that way making it possible to incorporate a highconcentration of the drug. In the latter case said formulation isstabilized by any of the above mentioned conventional surfactants.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A shows the ¹³ C-NMR spectra of an emulsion with CMZ;

FIG. 1B shows the ¹³ C-NMR spectra of an emulsion without CMZ;

FIG. 2 shows changes in the chemical shifts of the carbonyl carbons of aphospholipid, located at the interface between oil and water in theemulsion system, in the presence of CMZ; and

FIG. 3 shows the effects of shift differences as essentially independentof temperature.

The location of the drug in the formulation in the former case can beestablished by known techniques such as ¹³ C-NMR and a spectra of anemulsion with and without CMZ is shown in FIG. 1. Using ¹³ C-NMRchemical shift determinations, it is possible to obtain information onthe location of the CMZ-molecule in the emulsion system. For example,according to FIG. 2 the chemical shifts of the carbonyl carbons of aphospholipid, which are located at the interface in the emulsion system,is changed in the presence of CMZ. In fact, there is a linearrelationship between the concentration of CMZ in the system and thechange in the chemical shifts of the carbonyl carbons (FIG. 2). Thechemical shifts of the methylene carbons, being located in the core ofthe emulsion droplets is essentially unaffected by the presence of CMZwhich can also be seen in FIG. 2. Notably, the effects of CMZ on theseshift differences are essentially independent of temperature, as shownin FIG. 3. Since the chemical shift of a nucleus depends on itsimmediate environment ( ≦5 Å), these findings clearly show that CMZ isprimarily located in the surface region of the emulsion droplets.

Surprisingly, it has been found that the presence ofemulsion-stabilizing surface active drugs at the interface of anemulsion not only produces emulsions with excellent physical stabilitybut also makes it possible to improve poor chemical stability of thedrug in some cases, rendering it possible to prolong storage of thesenovel formulations of e.g. CMZ and/or any of the analogues or any otherappropriate drug at room temperature. Improved chemical stability of thedrug as well as a good physical stability of the formulation have alsobeen obtained when e.g. CMZ and/or any of the analogues or any otherappropriate drug which is in the liquid state has been used as theactual oil phase of an emulsion, thus allowing for a prolonged storageat room temperature. It has also become possible to substantiallyincrease the drug concentration in these systems compared to a watersolution of the drug and at the same time maintaining a physiologicallyacceptable pH thereby rendering these novel formulations clinically moreuseful. It has furthermore become possible to replace glucose withglycerol, which is not contraindicated in the treatment and/orprevention of neurodegeneration. Many of the above mentioned surfaceactive drugs are known to cause hemolysis as well as thrombophlebitiswhen administered parenterally as water solutions. Consequently, it wasmost surprising and clinically important when it was found that thesenovel formulations according to the present invention made it possibleto greatly reduce the incidence of hemolysis and thrombophlebitis andeven in some cases made the symptoms to completely disappear withoutreducing the pharmacological effect of the drug. In addition to this anumber of other clinically and pharmaceutically undesirable propertieswere successfully dealt with by using the novel formulation according tothe present invention. Hence, the safety of e.g. CMZ in the clinic wasimproved by a substantially reduced sorption of the drug by intravenousinfusion giving sets and moreover by giving the emulsion orally it wasfound that this type of formulation was also capable of improving theconventional liquid oral dosage form by a considerably better masking ofthe bitter taste of CMZ and at the same time solving the problem of theacidity of the syrup.

Another object of the present invention is a process for the preparationof the novel formulation comprising the following steps;

in the case where the emulsion-stabilizing surface active drug is notitself used as the internal oil phase by

adding the emulsion-stabilizing surface active drug and an optionalconventional surfactant to a two-phase, oil-water-system at roomtemperature;

allowing the emulsion-stabilizing surface active drug or theemulsion-stabilizing surface active drug together with the conventionalsurfactant to equilibrate at the interface;

adding an agent giving isotonicity to the final formulation; and

homogenizing by high pressure technique whereby a stable emulsion isobtained which has a droplet size distribution where the main fractionis below 200 nm;

or in the case where the drug functions as the internal oil phase of thesystem by

dispersing the emulsion-stabilizing surface active drug together with aconventional surfactant in water at room temperature;

allowing said surfactant to equilibrate at the interface;

adding an agent giving isotonicity to the final formulation; and

homogenizing by high pressure technique; whereby a stable emulsion isobtained which has a droplet size distribution where the main fractionis below 200 nm.

The resulting formulation is easily sterile filtered. Instead of water asodium carbonate buffer may be used.

If the drugs are sensitive to heat, a prerequisite is that these systemscan readily be: a) sterile filtered which means that the main fractionof the size distribution of the droplets must be below 200 nm,preferably below a 100 nm (determined by dynamic light scattering, b)prepared without the addition of heat, which is usually required in aprocess like this (typically 60°-70° C.). Hence, by the inherentcharacteristics of the novel formulation according to the presentinvention it is possible to prepare these systems at room temperaturewith a mean droplet size below 100 nm (allowing sterile filtration)without the additional help of solvents or co-solvents during theprocess of manufacturing.

This novel formulation comprises in general the emulsion-stabilizingsurface active drug in a concentration from about 0.01 to 5% w/v.

More particularly, the novel formulation of the invention comprises: a)the emulsion-stabilizing surface active drug in an amount of from about0.01 to 5.0 g per 100 ml of the final formulation; b) if the drug is notitself used as the internal oil phase a pharmacologically inert oil maybe used in an amount of from about 0.5 to 40 g per 100 ml of the finalformulation, said oil being selected from any pharmaceuticallyacceptable oils, such as soybean oil, safflower oil, sesame oil, peanutoil, cottonseed oil, borago oil, sunflower oil, corn oil, olive oil,medium chain triglycerides (such as Miglyol®), or acetylatedmonoglycerides; c) a surfactant in an amount of from about 0.1 to 20 gper 100 ml of the final formulation, said surfactant being selected fromany pharmaceutically acceptable non-ionic surfactants, such as thepoloxamers F68, F127 or L92 or polyoxyethylene sorbitan fatty acidesters, polyoxyethylene stearates or sorbitan fatty acid esters; butpreferably together with phospholipids, such as egg yolk phospholipids,soya phospholipids, synthetic phosphatidylcholines (e.g.dimyristoyl-phosphatidylcholine (DMPC) and/ordipalmitoyl-phosphatidylcholine (DPPC)) or purifiedphosphatidyl-cholines of vegetable origin; or any other suitablesurfactants acceptable to regulatory agencies (GRAS status); d) waterfor injection or suitable buffer; e) preferred agents to giveisotonicity to the final formulation are glycerol and/or sorbitol.

The amount of CMZ-base and/or analogues is conveniently from about 0.5to 3.0 g per 100 ml of the final formulation, preferably 0.5 to 2.0 gper 100 ml of the final formulation. The amount of a pharmacologicallyinert oil, if any, is conveniently from about 2.0 to 30 g per 100 ml ofthe final formulation, preferably 2.0 to 20 g per 100 ml of the finalformulation. The amount of surfactant, if any, is conveniently fromabout 1.0 to 10 g per 100 ml of the final formulation, preferably 2.0 to5.0 g per 100 ml of the final formulation. The amount of the isotonicityagent is from about 1.0 to 5.0 g per 100 ml of the final formulation.

The administration in the novel method of treatment of this inventionmay conveniently be oral or parenteral at a dosage level of, forexample, about 1 to 3000 mg/kg, preferably about 10 to 1000 mg/kg andespecially about 25 to 250 mg/kg and may be administered on a regimen of1 to 4 doses or treatments per day. The dose will depend on the route ofadministration preferred routes being oral or intravenousadministration. It will be appreciated that the severity of the disease,the age of the patient and other factors normally considered by theattending physician will influence the individual regimen and dosagemost appropriate for a particular patient.

In an acute situation, this novel method of treatment may also involveparenteral administration of the drug in the form of prepacked unitdoses.

Preferred embodiments of the invention will now be described by way ofexample, which however are not limitative:

EXAMPLES 1-2

Oil-in-water emulsions of CMZ for intravenous and oral use were preparedfrom the following components:

    ______________________________________                                                               Ex. 1                                                  ______________________________________                                        CMZ                    0.5 g                                                  DMPC                   2.0 g                                                  DPPC                   0.5 g                                                  Miglyol 812            2.5 g                                                  Glycerol               4.0 g                                                  Water for injection to 100 ml                                                 Adjustment to physiological pH with 1M                                        sodium hydroxide.                                                             ______________________________________                                                               Ex. 2                                                  ______________________________________                                        CMZ                    0.5 g                                                  DMPC                   2.0 g                                                  DPPC                   0.5 g                                                  Miglyol 812            2.5 g                                                  Glycerol               2.0 g                                                  Sodium carbonate buffer pH 7.0 to                                                                    100 ml                                                 ______________________________________                                    

In a first step the emulsion-stabilizing drug and a surfactant wereadded to a two-phase system, oil-water, at room temperature and weresubsequently allowed to equilibrate at the interface. This formulation,together with additional indicated components in the formula, washomogenized and the resulting emulsion was stable and had an averagedroplet size below 100 nm and could easily be sterile filtered (200 nmfilter).

EXAMPLES 3-8

Oil-in-water emulsions were prepared as described in Examples 1-2 withthe following components:

    ______________________________________                                                            Ex. 3   Ex. 4    Ex. 5                                    ______________________________________                                        5-(2-chloroethyl)-4-methyloxazole                                                                 0.05 g  2.0 g    4.0 g                                    DMPC                0.4 g   2.0 g    4.0 g                                    DPPC                0.1 g   0.5 g    1.0 g                                    Miglyol 812         1.0 g   5.0 g    10.0 g                                   Glycerol            5.0 g   3.0 g    2.5 g                                    Water for injection to                                                                            100 ml  100 ml   100 ml                                   Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                            Ex. 6   Ex. 7    Ex. 8                                    ______________________________________                                        CMZ                 0.05 g  2.0 g    4.0 g                                    DMPC                0.4 g   2.0 g    4.0 g                                    DPPC                0.1 g   0.5 g    1.0 g                                    Miglyol 812         1.0 g   5.0 g    10.0 g                                   Glycerol            2.5 g   1.5 g    1.25 g                                   Sodium carbonate buffer pH 7.0 to                                                                 100 ml  100 ml   100 ml                                   ______________________________________                                    

EXAMPLES 9-12

Oil-in-water emulsions were prepared as described in Examples 1-2 withthe following components:

    ______________________________________                                                               Ex. 9                                                  ______________________________________                                        5-(2-chloroethyl)-2,4-dimethyloxazole                                                                2.0 g                                                  DMPC                   2.0 g                                                  DPPC                   0.5 g                                                  Soybean oil            5.0 g                                                  Glycerol               3.0 g                                                  Water for injection to 100 ml                                                 Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                               Ex. 10                                                 ______________________________________                                        CMZ                    2.0 g                                                  DMPC                   2.0 g                                                  DPPC                   0.5 g                                                  Safflower oil          5.0 g                                                  Glycerol               3.0 g                                                  Water for injection to 100 ml                                                 Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                               Ex. 11                                                 ______________________________________                                        5-(2-chloroethyl)-2,4-dimethylthiazole                                                               2.0 g                                                  DMPC                   2.0 g                                                  DPPC                   0.5 g                                                  Cotton seed oil        5.0 g                                                  Glycerol               3.0 g                                                  Water for injection to 100 ml                                                 Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                               Ex. 12                                                 ______________________________________                                        CMZ                    2.0 g                                                  DMPC                   2.0 g                                                  DPPC                   0.5 g                                                  Soy bean oil           5.0 g                                                  Acetylated monoglycerides                                                                            2.5 g                                                  Glycerol               3.0 g                                                  Water for injection to 100 ml                                                 Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                    

EXAMPLES 13-16

Oil-in-water emulsions, according to Examples 9-12, were prepared withthe only difference that a sodium carbonate buffer pH 7.0 was used to afinal volume of 100 ml instead of water for injection and the amount ofglycerol was reduced to 1.5 g per 100 ml of the final formulations.EXAMPLES 17-20

Oil-in-water emulsions were prepared as described in Examples 1-2 withthe following components:

    ______________________________________                                                                Ex. 17                                                ______________________________________                                        5-(2-chloro-1-hydroxyethyl)-4-methylthiazole                                                          2.0 g                                                 Egg yolk phospholipids  2.5 g                                                 Miglyol 812             5.0 g                                                 Glycerol                3.0 g                                                 Water for injection to  100 ml                                                Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                                Ex. 18                                                ______________________________________                                        CMZ                     2.0 g                                                 Soya phospholipids      2.5 g                                                 Miglyol 812             5.0 g                                                 Glycerol                3.0 g                                                 Water for injection to  100 ml                                                Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                                Ex. 19                                                ______________________________________                                        Felodipine*             0.1 g                                                 Soy phosphatidylcholine 2.5 g                                                 Soy bean oil            10.0 g                                                Glycerol                2.5 g                                                 Water for injection to  100 ml                                                Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                                Ex. 20                                                ______________________________________                                        CMZ                     2.0 g                                                 Poloxamer F68           2.5 g                                                 Miglyol 812             5.0 g                                                 Glycerol                3.0 g                                                 Water for injection to  100 ml                                                Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                         *Felodipine is                                                                4(2,3-Dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic       acid ethyl methyl ester.                                                 

EXAMPLES 21-24

Oil-in-water emulsions were prepared according to Examples 17-20 withthe only difference that a sodium carbonate buffer pH 7.0 was used to afinal volume of 100 ml instead of water for injection and the amount ofglycerol was reduced to 1.5 g per 100 ml of the final formulations.

EXAMPLES 25-26

Oil in water emulsions, where the emulsion-stabilizing drug was used asthe sole stabilizing agent in the system, were prepared from thefollowing components:

    ______________________________________                                                               Ex. 25                                                 ______________________________________                                        CMZ                    0.5 g                                                  Miglyol 812            2.5 g                                                  Glycerol               4.0 g                                                  Water for injection to 100 ml                                                 Adjustment to physiological pH with 1M                                        sodium hydroxide.                                                             ______________________________________                                                               Ex. 26                                                 ______________________________________                                        CMZ                    0.5 g                                                  Miglyol 812            2.5 g                                                  Glycerol               2.0 g                                                  Sodium carbonate buffer pH 7.0 to                                                                    100 ml                                                 ______________________________________                                    

In a first step the emulsion-stabilizing drug was added to a two-phasesystem, oil-water, at room temperature and was subsequently allowed toequilibrate at the interface. This formulation, together with additionalindicated components in the formula, was homogenized and the resultingemulsion was stable and had an average droplet size below 100 nm andcould easily be sterile filtered (200 nm filter).

EXAMPLES 27-30

Oil in water emulsions were prepared as described in Examples 25-26 withthe following components:

    ______________________________________                                                                Ex. 27                                                ______________________________________                                        5-(2-chloro-1-hydroxyethyl)-4-methylthiazole                                                          2.0 g                                                 Miglyol 812             5.0 g                                                 Glycerol                3.0 g                                                 Water for injection to  100 ml                                                Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                                Ex. 28                                                ______________________________________                                        CMZ                     2.0 g                                                 Miglyol 812             5.0 g                                                 Glycerol                3.0 g                                                 Water for injection to  100 ml                                                Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                                Ex. 29                                                ______________________________________                                        5-(2-chloroethyl)-4-methyloxazole                                                                     2.0 g                                                 Miglyol 812             5.0 g                                                 Glycerol                3.0 g                                                 Water for injection to  100 ml                                                Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                                Ex. 30                                                ______________________________________                                        CMZ                     2.0 g                                                 Miglyol 812             5.0 g                                                 Glycerol                3.0 g                                                 Water for injection to  100 ml                                                Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                    

EXAMPLES 31-32

Emulsions where the drug functions as the internal oil-phase of thesystem were prepared from the following components:

    ______________________________________                                                               Ex. 31                                                 ______________________________________                                        CMZ                    0.5 g                                                  DMPC                   2.0 g                                                  DPPC                   0.5 g                                                  Glycerol               4.0 g                                                  Water for injection to 100 ml                                                 Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                               Ex. 32                                                 ______________________________________                                        5-(2-chloroethyl)-2,4-dimethyloxazole                                                                0.5 g                                                  DMPC                   2.0 g                                                  DPPC                   0.5 g                                                  Glycerol               2.0 g                                                  Sodium carbonate buffer pH 7.0 to                                                                    100 ml                                                 ______________________________________                                    

In a first step the drug was dispersed in water at room temperature. Anemulsion was then prepared from the resulting drug-water dispersion,together with additional indicated components in the formula. Theresulting emulsion was stable and had an average droplet size below 100nm and could easily be sterile filtered (200 nm filter).

EXAMPLES 33-38

Emulsions according to Examples 31-32 were prepared with the followingcomponents:

    ______________________________________                                                            Ex. 33  Ex. 34   Ex. 35                                   ______________________________________                                        CMZ                 0.05 g  2.0 g    4.0 g                                    DMPC                0.4 g   2.0 g    4.0 g                                    DPPC                0.1 g   0.5 g    1.0 g                                    Glycerol            5.0 g   3.0 g    2.5 g                                    Water for injection to                                                                            100 ml  100 ml   100 ml                                   Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                            Ex. 36  Ex. 37   Ex. 38                                   ______________________________________                                        5-(2-chloroethyl)-2,4-dimethylthiazole                                                            0.05 g  2.0 g    4.0 g                                    DMPC                0.4 g   2.0 g    4.0 g                                    DPPC                0.1 g   0.5 g    1.0 g                                    Glycerol            2.5 g   1.5 g    1.25 g                                   Sodium carbonate buffer pH 7.0 to                                                                 100 ml  100 ml   100 ml                                   ______________________________________                                    

EXAMPLES 39-42

Emulsions according to Examples 31-32 were prepared with the followingcomponents:

    ______________________________________                                                                Ex. 39                                                ______________________________________                                        CMZ                     2.0 g                                                 Egg yolk phospholipids  2.5 g                                                 Glycerol                3.0 g                                                 Water for injection to  100 ml                                                Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                                Ex. 40                                                ______________________________________                                        5-(2-chloro-1-hydroxyethyl)-4-methylthiazole                                                          2.0 g                                                 Soya phospholipids      2.5 g                                                 Glycerol                3.0 g                                                 Water for injection to  100 ml                                                Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                                Ex. 41                                                ______________________________________                                        CMZ                     2.0 g                                                 Soy phosphatidylcholine 2.5 g                                                 Glycerol                3.0 g                                                 Water for injection to  100 ml                                                Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                                                Ex. 42                                                ______________________________________                                        CMZ                     2.0 g                                                 Pluronic F68            2.5 g                                                 Glycerol                3.0 g                                                 Water for injection to  100 ml                                                Adjustment to physiological pH with 1M                                        sodium hydroxide                                                              ______________________________________                                    

EXAMPLES 43-46

Emulsions according to Examples 39-42 were prepared with the onlydifference that a sodium carbonate buffer pH 7.0 was used to a finalvolume of 100 ml instead of water for injection and the amount ofglycerol was reduced to 1.5 g per 100 ml of the final formulations.

What is claimed is:
 1. A sterile pharmaceutical formulation of anoil-in-water emulsion for parenteral and oral administration whichcomprises:(i) an emulsion-stabilizing surface active drug in aconcentration ranging from 0.01 g to 5.0 g per 100 ml of the finalformulation; (ii) a pharmacologically inert oil when the drug is not aninternal oil; (iii) a surfactant when the drug is an internal oil; (iv)water or a buffer; and (v) an agent giving isotonicity to the finalformulation; the formulated emulsion having a major fraction of stabledroplets having a size below 200 nm so as to be suitable for sterilefiltering before use.
 2. The formulation according to claim 1 whereinthe emulsion-stabilizing surface active drug is a drug for preventingneurodegeneration, treating neurodegeneration, or having ananti-convulsant or sedative-hypnotic effect.
 3. The formulationaccording to claim 1 wherein the emulsion-stabilizing surface activedrug is selected from the group consisting of5-(2-chloroethyl)-4-methylthiazole, 5-(2-chloroethyl)-4-methyloxazole,5-(2-chloroethyl)-2,4-dimethyloxazole,5-(2-chloroethyl)-2,4-dimethylthiazole,5-(2-chloro-1-hydroxyethyl)-4-methylthiazole and its optical isomers. 4.The formulation according to claim 3 wherein the emulsion-stabilizingsurface active drug is 5-(2-chloroethyl)-4-methylthiazole.
 5. Theformulation according to claim 1 wherein the pharmacologically inert oilpresent in an amount of from about 0.5 to 40 g per 100 ml of theformulation, is selected from the group consisting of soybean oil,safflower oil, sesame oil, peanut oil, cottonseed oil, borago oil,sunflower oil, corn oil, olive oil, medium chain triglycerides andacetylated monoglycerides.
 6. The formulation according to claim 1wherein the surfactant is used in an amount of from about 0.1 to 20 gper 100 ml of the final formulation and selected from the groupconsisting of a pharmaceutically acceptable non-ionic surfactant,phospholipid and any other suitable surfactant acceptable to regulatoryagencies.
 7. The formulation according to claim 1 wherein the agentgiving isotonicity to the final formulation is glycerol and/or sorbitol.8. The formulation according to claims 1-3 or 4, wherein the amount ofthe drug is from about 0.5 g to 3.0 g per 100 ml of the finalformulation.
 9. The formulation according to claims 1-3 or 4, whereinthe amount of the drug is from about 0.5 g to 2.0 g per 100 ml of thefinal formulation.
 10. The formulation according to claim 1, wherein theoil is present in an amount of from about 2.0 g to 30 g per 100 ml ofthe final formulation.
 11. The formulation according to claim 1, wherethe oil is present in an amount from 2.0 g to 20 g per 100 ml of thefinal formulation.
 12. The formulation according to claim 1, wherein thesurfactant is present in an amount of from about 1.0 g to 10 g per 100ml of the final formulation.
 13. The formulation according to claim 1,wherein the surfactant is present in an amount of from 2.0 g to 5.0 gper 100 ml of the final formulation.
 14. A sterile pharmaceuticalemulsion preparation for parenteral or oral administration comprising anemulsion-stabilizing surface active drug in base form which is dispersedand equilibrated in a two-phase, oil-water-system which furthercomprises a pharmacologically inert oil or surfactant; a sufficientamount of an agent for isotonicity;the preparation being homogenizedunder high pressure so as to obtain an emulsion which has a droplet sizedistribution where the main fraction is below 200 nm; and sterilefiltered through a 0.2 micron particle cut-off membrane filter.